The pathogenesis of JMML has been linked to dysregulated GM-CSF growth factor signal transduction through the Ras pathway, with abnormalities identified in the RAS and NF1 genes in this pathway. This dysregulation results in JMML cells demonstrating selective hypersensitivity to GM-CSF in vitro. One of the new treatment modalities in JMML, 13-cis retinoic acid therapy, appears to modulate this GM-CSF hypersensitivity. A new multi-modality treatment protocol for JMML has recently been approved by the CTEP branch of the NCI. This protocol will be administered through the Children's Oncology Group and is a phase II window/phase III trial. Experimental therapy with a farnesyl transferase inhibitor will be tested in the phase II window, followed by 13-cis retinoic acid, chemotherapy, and stem cell transplantation in the phase III portion. One of the many advantages of this type of trial design is that it permits the rigorous evaluation of the efficacy of a single agent in untreated JMML patients who have not developed drug resistance. If one phase II agent tails, the protocol is designed to allow for the substitution of a different agent without disrupting the rest of the study. Three experimental agents can be nearly fully tested during the course of the phase III trial. Laboratory studies will evaluate whether they are truly acting as mechanism-based therapeutics. The principal aims of this application are to utilize the patient resources from this protocol as a conduit for accruing cases to address several key clinical and basic science investigations including: 1) to test the efficacy of the famesyl transferase inhibitor, Rl15777, in untreated JMML patients, 2) to utilize this phase II window approach to evaluate other molecularly targeted, mechanism-based therapeutics for JMML, and 3) to determine the actual frequency of NFI and RAS gene abnormalities in JMML patients and correlate these results with known clinical prognostic markers to determine if therapeutically relevant, biologically-defined subsets of JMML exist, towards which future mechanism-based therapies can be specifically directed. Thus, the translational experiments proposed in this application are based on our understanding of JMML pathogenesis, and will provide novel data about the pharmacodynamics of targeted therapeutics. Beyond JMML, these studies may uncover agents that inhibit Ras that ultimately prove to be broadly applicable to other myeloid malignancies and to a broad range of human cancers.